JAssistReprodGenet DOI 10.1007/s10815-017-0911-9

GENETICS

Involvement of 17β-hydroxysteroid dehydrogenase type 1 937 A>G polymorphism in infertility in Polish Caucasian women with endometriosis

Maciej Osiński1 & Adrianna Mostowska2 & Przemyslaw Wirstlein1 & Jana Skrzypczak1 & Paweł Piotr Jagodziński2 & Malgorzata Szczepańska1

Received: 31 August 2016 /Accepted: 17 March 2017 # The Author(s) 2017. This article is published with open access at Springerlink.com

Abstract Methods The genotyping of cases (n = 290) and fertile wom- Purpose Endometriosis is considered to be an - en (n = 410) was conducted by high-resolution melting curve related chronic inflammatory disease. The 17β- analysis. hydroxysteroid dehydrogenase 1 (HSD17B1) converts es- Results Statistical analysis demonstrated that the HSD17B1 trone to 17β . The role of HSD17B1 937 A>G 937 A>G SNP is associated with endometriosis in stages I (rs605059) single nucleotide polymorphism (SNP) in devel- and II. The ptrend and pallelic values calculated for the opment of endometriosis is still disputable. This study evalu- HSD17B1 937 A>G polymorphism were statistically signifi- ated the association of the HSD17B1 937 A>G (rs605059) cant and were equal to 0.001 and 0.0009, respectively. There SNP with infertile women affected by endometriosis from was a significant association for the dominant model: (AG + Polish Caucasian population. GG vs AA) OR = 1.973 (95% CI = 1.178–3.304), p =0.009, and for the recessive model: (GG vs AG + AA) OR = 1.806 (95% CI = 1.178–2.770), p =0.006. However, we did not find statistical association of HSD17B1 937 A>G polymorphism Electronic supplementary material The online version of this article with all infertile women with endometriosis or infertile wom- (doi:10.1007/s10815-017-0911-9) contains supplementary material, en with endometriosis in stages III and IV. which is available to authorized users. Conclusion Our genetic study demonstrated HSD17B1 937 G variant as a risk factor for infertility in women with stage I and * Malgorzata Szczepańska II endometriosis in Polish Caucasian patients. [email protected] Maciej Osiński Keywords Endometriosis . HSD17B1 . Polymorphism [email protected]

Adrianna Mostowska [email protected] Introduction Przemyslaw Wirstlein [email protected] Endometriosis is a benign disease affecting women of childbearing age, which is characterized by the presence Jana Skrzypczak [email protected] of ectopic endometrial implants outside the uterine cavity [1]. These implants are found in the pelvis, uterosacral Paweł Piotr Jagodziński [email protected] ligaments, ovaries, rectovaginal septum, and pouch of Douglas. This disorder affects 5–10%ofwomeninrepro- – 1 Department of Obstetrics, Gynecology and Gynecological Oncology, ductive age, with incidence of 30 50% in infertile women Division of Reproduction, Poznan University of Medical Sciences, [2–4]. The exact pathogenesis of endometriosis is still 33 Polna St, 60-535 Poznań, Poland unclear. Retrograde menstruation is recognized as a pos- 2 Department of Biochemistry and Molecular Biology, Poznan sible mechanism in the development of this disease. The University of Medical Sciences, Poznan, Poland retrograde menstruation is observed in 90% of women of J Assist Reprod Genet childbearing age; however, merely 10% of women ap- Reproduction at Poznan University of Medical Sciences, peared to develop endometriosis [5]. Poland. A case-control study design was used in 290 patients This suggests that several factors are involved in the with endometriosis and 410 matched controls (Table 1). The pathogenesis of endometriosis, which increase persis- patients with infertility and endometriosis underwent laparos- tence of the endometriotic lesions. Both the occurrence copy and had a histologically confirmed diagnosis at the and progression of endometriosis are related to abnormal Gynecologic and Obstetrical University Hospital, Division expression of proteins involved in angiogenesis, cell of Reproduction at Poznan University of Medical Sciences, growth, immune response, reduced progestin, and in- Poland. Patients with endometriosis were divided into two creased estrogenic activity [6]. subgroups according to the revised American Society for Endometriosis is considered as an estrogen-related chronic Reproductive Medicine (rASRM) classification system [16]; inflammatory disease [4]. There is increased evidence demon- n = 126 patients (43.45%) had minimal or mild endometriosis strating that endometriotic implants contain aromatase, which (stages I–II) and n = 157 (54.14%) had moderate or severe converts to estrogen [4, 6–8]. endometriosis (stages III–IV); n = 7 (2.41%) patients had un- Recent studies have demonstrated the presence of 17β- defined stage of endometriosis (Table 1). The control group hydroxysteroid dehydrogenase (HSD17Bs) enzyme family ex- was encompassed of healthy women (n = 410), without his- pression in endometriotic lesions. HSD17Bs are involved in tory of infertility, who had a cesarean section performed either the oxidation or reduction of sex steroids [9]. HSD17B1 (Table 1). carries out the conversion of (E1) to 17β estradiol (E2), The inclusion and exclusion criteria for the infertile women which is a more biologically active estrogen [9]. with endometriosis and the women without the disease were It has been suggested that genetic variants of HSD17B1, previously described [17]. Inclusion criteria for infertile wom- specifically the 937 A>G (rs605059) single nucleotide poly- en with diagnosed endometriosis were regular menses, no morphism (SNP), may contribute to endometriosis [10, 11]. anatomical changes in the reproductive tract, no hormonal This transition is located in exon 6 and alters serine to glycine treatments, and a minimum of 1 year of infertility with a cur- at position 312 [12, 13]. Studies conducted to this day incon- rent desire for conception. Exclusion criteria were mechanical sistently demonstrated HSD17B1 937 A>G SNP as a genetic distortion of the endometrial cavity by fibroids, bilateral tubal risk factor of endometriosis [10, 11, 14, 15]. Therefore, our occlusion, male factor infertility, adenomyosis, polycystic study aimed to evaluate the contribution of HSD17B1 937 ovary syndrome (PCOS), and benign or malignant gynecolog- A>G SNP to infertility in women with endometriosis in the ical diseases. All included patients with endometriosis had Polish population. laparoscopic and histological diagnosis of endometriosis. Inclusion criteria for fertile control women were cesarean sec- tion performed, regular menses, no anatomical changes in the Materials and methods reproductive tract, no hormonal treatments, and at least one child born no more than 1 year before study (Table 1). Study population Exclusion criteria were signs of past or present inflammation, pelvic abnormalities, endometriosis, adenomyosis, PCOS, or Peripheral blood samples were obtained from infertile women any other benign or malignant gynecological diseases, which with endometriosis and control women of similar age from the was confirmed during surgical exploration. Both patients with Gynecologic and Obstetrical University Hospital, Division of endometriosis and healthy controls were all Caucasians of

Table 1 Characteristicsofthe populations of infertile women Characteristics Infertile women with endometriosis Fertile healthy women with endometriosis and fertile healthy women Numbers 290 410 Age (years) 33 (21–37)a 32 (18–37)a Parity NA 1 (1–5)a Duration of infertility (years) 3 (1–8)a NA rASRM (stage)b Stages I and II (n =126) NA Stages III and IV (n =157) Undefined (n =7)

NA not applicable a Median (range) b Revised American Society for Reproductive Medicine (rASRM) [16] JAssistReprodGenet

Polish ancestry (Table 1).Written informed consent was ob- with all infertile women with endometriosis. The ptrend and tained from all participating individuals. The study was con- pallelic values computed for HSD17B1 937 A>G SNP were ducted in accordance with the code of ethics of the Declaration not statistically significant and were equal to 0.195 and of Helsinki and obtained the approval of the Local Ethical 0.181, respectively. The OR for dominant model: (AG + GG Committee of Poznan University of Medical Sciences. vs AA) was 1.152 (95% CI = 0.819–1.619), p =0.416,and OR for recessive model: (GG vs AG + AA) was 1.260 (95% Genotyping CI = 0.896–1.771), p =0.184.

Genomic DNA was isolated from peripheral blood leukocytes The comparison of HSD17B1 937 A>G genotype by salt extraction. Genotyping was conducted by high- and allele frequencies between infertile women resolution melting (HRM) curve analysis on the LightCycler with endometriosis in stages I and II and fertile healthy 480 system (Roche Diagnostics, Mannheim, Germany). women Genomic DNA was amplified with the use of specific primers F: CCTGGGGCAGAGGACGAG and R: AAGAAGGG The prevalence of the genotype and allele frequencies, OR, CGCGGGAGAC. The annealing temperature was 66 °C and 95% CI computed for the HSD17B1 937 A>G for both and the PCR product size was 113 bp. Amplified DNA frag- fertile healthy women and women with endometriosis stages I ments were then subjected to HRM with 0.1 °C increments in and II are stated in Table 2.Theptrend and pallelic values calcu- temperatures ranging from 85 to 98 °C. The genotyping qual- lated for the HSD17B1 937 A>G polymorphism were statis- ity was evaluated by repeated genotyping of 10% randomly tically significant and were equal to 0.001 and 0.0009, respec- selected samples. tively. We observed significant association for the dominant model: (AG + GG vs AA) OR = 1.973 (95% CI = 1.178– Data analysis 3.304), p = 0.009, and for recessive model: (GG vs AG + AA) OR = 1.806 (95% CI = 1.178–2.770), p = 0.006. A power Hardy-Weinberg equilibrium (HWE) was assessed by analysis predicted sufficient power to detect an association of Pearson’s goodness-of-fit chi-square (χ2) statistic. The SNP the HSD17B1 937 A>G polymorphism with a genetic effect was studied for associations with endometriosis using the of 1.9 or more for the recessive and a genetic effect of 2.1 or Cochran-Armitage trend test. Differences in the allele and more for the dominant model in infertile women with endo- genotype frequencies between the cases and controls were metriosis in stages I and II (Supplementary file 1). calculated using χ2 analysis. The odds ratio (OR) and asso- ciated 95% confidence intervals (95% CI) were also com- The comparison of HSD17B1 937 A>G genotype puted. The p values <0.05 were considered as statistically and allele frequencies between infertile women significant. Power calculations were evaluated using Quanto with endometriosis in stages III and IV and fertile healthy software (Gauderman WJ, Morrison JM. QUANTO 1.2: a women computer program for power and sample size calculations for genetic-epidemiology studies, URL http://biostats.usc. The prevalence of the genotype and allele frequencies, OR, edu/software). and 95% CI computed for the HSD17B1 937 A>G for both fertile healthy women and women with endometriosis stages III and IV are stated in Table 2. There was no observed con- Results tribution of HSD17B1 937 A>G to endometriosis to stages III and IV, and the ptrend and pallelic values were not statistically The comparison of HSD17B1 937 A>G genotype significant and were equal to 0.326 and 0.313, respectively and allele frequencies between all infertile women (Table 2). The OR for dominant model: (AG + GG vs AA) with endometriosis in stages I, II, III, and IV and fertile was OR = 0.820 (95% CI = 0.551–1.220), p = 0.327, and for healthy women recessive model: (GG vs AG + AA) was OR = 0.868 (95% CI = 0.558–1.351), p =0.531. The distribution of HSD17B1 937 A>G genotypes did not differ from HWE between patients (p = 0.378) and controls (p = 0.665) for all women with endometriosis. The prevalence Discussion of the genotype and allele frequencies, OR, and 95% CI com- puted for the HSD17B1 937 A>G for both fertile healthy The physiological role of E2 in the menstrual cycle has al- women and all women with endometriosis stages I, II, III, ready been well determined [18]. Estrogen is the main steroid and IV are stated in Table 2. Statistical analysis demonstrated of the proliferative phase of the reproductive cycle [18]. E2 that the HSD17B1 937 A>G polymorphism is not associated initiates a significant proliferation of the endometrial tissue J Assist Reprod Genet

Table 2 HSD17β1 937 A>G (s605059) polymorphism as the risk of all stages cumulatively, stages I and II, and stages III and IV of endometriosis when compared with fertile healthy women

Cases Controls

a a Stage of Genotypes Alleles Genotypes Alleles ptrend pallelic ORAG+GGvsAA ORGGvsAG+AA endometriosis value value (95% (95% No. Freq. No. Freq. No. Freq. No. Freq. CI)b; p valued CI)c; p valued

All stages AA 74 0.25 A 281 0.48 AA 116 0.28 A 427 0.52 0.195 0.181 1.152 (0.819– 1.260 (0.896– n =290 AG 133 0.46 G 299 0.52 AG 195 0.48 G 393 0.48 1.619); 0.416 1.771); 0.184 GG 83 0.29 GG 99 0.24 Stages I AA 21 0.17 A 101 0.40 AA 116 0.28 A 427 0.52 0.001 0.0009 1.973 (1.178– 1.806 (1.178– and II AG 59 0.47 G 151 0.60 AG 195 0.48 G 393 0.48 3.304); 0.009 2.770); 0.006 n =126 GG 46 0.36 GG 99 0.24 Stages III AA 51 0.32 A 174 0.55 AA 116 0.28 A 427 0.52 0.326 0.313 0.820 (0.551– 0.868 (0.558– and IV AG 72 0.46 G 140 0.45 AG 195 0.48 G 393 0.48 1.220); 0.327 1.351); 0.531 n =157 GG 34 0.22 GG 99 0.24

For seven cases, the stage of endometriosis is unknown. Significant results are in italics a Underline denotes the minor allele (MA) b Dominant model (G is the risk allele) c Recessive model (G is the risk allele) d Chi-square analysis and supports the growth of the endometrial glands before ovu- I–II disease, in Estonian population [10]. Our findings are also lation, preparing endometrium for the action of progesterone inconsistent with Tsuchiya et al. (2005) who demonstrated [18]. However, abnormal production of estrogen contributes contribution of A allele of HSD17B1 to endometriosis at to various estrogen-related diseases including endometriosis stages III and IV [11]. There are studies which did not find [19, 20]. The significant function of E2 in the development of association of HSD17B1 937 A>G polymorphism with endo- this disease has been well documented in animal models includ- metriosis [15, 16]. The study conducted in Taiwanese Han and ing rodent and baboon models [21, 22]. More endometriotic Brazilian population also did not indicate HSD17B1 937 A>G lesions were developed in E2-treated mice than control animals SNP contribution to endometriosis [15, 30]. Trabert et al. [21]. Recently, Nair et al. employed antiprogestin treatment (2011) did not observe contribution of HSD17B1 rs2676530 which resulted in unopposed estrogenicity and development and rs676387 polymorphisms to endometriosis patients from of spontaneous endometriosis in baboons [22]. western Washington cohort, including Caucasian, African, There are many human studies that demonstrate upregula- and Asian American individuals [14]. A recent meta- tion of local estrogen production in endometriotic tissue, mainly analysis confirms lack of HSD17B1 rs605059 polymorphism by increased catalytic aromatase activity [6, 7, 23]. Moreover, association with endometriosis in the overall population as the endometriotic implants have increased E2 levels as com- well as in subgroup ethnicities [31]. The different effect of pared to E1 throughout the menstrual cycle [24]. The treatments HSD17B1 937 A>G on the development of endometriosis in of endometriosis include the reduction of to decrease distinct ethnicities may have also resulted from genetic het- their stimulatory effect on the endometrium. These treatments erogeneity, size of the studied groups, and different popula- include progestins, oral contraceptives, and antagonists of tions’ exposure to environmental factors. gonadotropin-releasing hormone [25, 26]. The differences between Estonian [10], Japanese [11], and The expression of different HSD17Bs including HSD17B1 our HSD17B1 937 gene variant association might be due to responsible for estrogen metabolism was well documented in linkage disequilibrium of rs605059 with an unknown SNP in eutopic and ectopic endometriotic tissue [27–29]. Inhibitors of Polish Caucasian population. Moreover, our study was con- HSD17B1 are considered in treatment of endometriosis [27]. In ducted in selected group of infertile women with endometri- our study, we found significant association of HSD17B1 937 G osis at stages I and II in which HSD17B1 937 G variant can be variant with infertile women having endometriosis in stages I a risk of infertility in our evaluated cohort. Recently, Ntostis and II, but not in all of the infertile women with endometriosis et al. (2015) has suggested HSD17B1 937 G variant being a or infertile women with endometriosis in stages III and IV. risk of recurrent spontaneous abortions [32]. Our results are contradictory to Lamp et al. (2010) who The disagreement in role of HSD17B1 937 A>G SNP in found HSD17B1 A variant as a risk of endometriosis at stage the development of other diseases has been demonstrated in JAssistReprodGenet different populations. They include development of the risk of Compliance with ethical standards Written informed consent was endometrial and breast cancer [31, 33–35]. The meta-analysis obtained from all participating individuals. The study was conducted in accordance with the code of ethics of the Declaration of Helsinki and did not show significant association between HSD17B1 obtained the approval of the Local Ethical Committee of Poznan rs605059 gene polymorphisms and risks of endometrial can- University of Medical Sciences. cer [31]. Additionally, the recent meta-analysis conducted by Open Access This article is distributed under the terms of the Creative Shi et al. (2016) suggested that the HSD17B1 937 G allele Commons Attribution 4.0 International License (http:// may protect from breast cancer development in Caucasians, creativecommons.org/licenses/by/4.0/), which permits unrestricted use, but not among Asians [35]. distribution, and reproduction in any medium, provided you give It has been demonstrated that women with severe stages of appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. the endometriosis displayed poor ovarian reserve, low oocyte and embryo quality, poor implantation, pelvic anatomy distor- tion, and mechanical disruptions such as pelvic adhesions References [36–38]. These abnormalities account for infertility, which is more likely to be found in women in severe stages of the 1. Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. endometriosis [39]. However, the possible mechanisms by Central changes associated with chronic pelvic pain and endome- which minimal/mild endometriosis impacts fertility is still elu- triosis. Hum Reprod Update. 2014;20:737–47. sive [40]. The overproduction of E2 has to be considered as a 2. Abu HH. Potential role of aromatase inhibitors in the treatment of causative factor of infertility in endometriosis [4, 6–8]. endometriosis. Int J Womens Health. 2014;6:671–80. HSD17B1 937 A>G SNP might be linked to changes in con- 3. McLeod BS, Retzloff MG. Epidemiology of endometriosis: an as- sessment of risk factors. Clin Obstet Gynecol. 2010;53:389–96. version of E1 to E2, which might account for infertility in 4. Guo SW, Wang Y. The prevalence of endometriosis in women with women with minimal/mild endometriosis. chronic pelvic pain. Gynecol Obstet Investig. 2006;62:121–30. Endometriosis is a multifactorial disease that is influenced 5. Burney RO, Giudice LC. Pathogenesis and pathophysiology of by multiple and a variety of environmental factors, in- endometriosis. Fertil Steril. 2012;98:511–9. cluding lifestyle [6]. It has been suggested that moderate and 6. Montgomery GW, Nyholt DR, Zhao ZZ, Treloar SA, Painter JN, Missmer SA, et al. The search for genes contributing to endometri- severe endometrioses have greater genetic burden than mini- osis risk. Hum Reprod Update. 2008;14:447–57. malormilddisease[41]. This may partially explain why 7. Bulun S, Zeitoun K, Takayama K, Sasano H. Molecular basis for HSD17B1 937 A>G SNP is associated with minimal/mild treating endometriosis with aromatase inhibitors. Hum Reprod – but not moderate/severe endometriosis, which in turn will Update. 2000;6:413 8. 8. Nothnick WB. The emerging use of aromatase inhibitors for endo- probably require a greater contribution of additional genetic metriosis treatment. Reprod Biol Endocrinol. 2011;9:87. and/or environmental factors for its etiology [41]. 9. Lukacik P, Kavanagh KL, Oppermann U. Structure and function of To date, the genetic risk factors for endometriosis-related human 17-hydroxysteroid dehydrogenases. Mol Cell Endocrinol. infertility have also included the ESR1, ESR2,andluteinizing 2006;248:61–71. hormone beta-subunit FOXP, complement component 3, lysyl 10. Lamp M, Peters M, Reinmaa E, Haller-Kikkatalo K, Kaart T, – Kadastik U, et al. Polymorphisms in ESR1, ESR2 and HSD17B1 oxidase-like protein 4,andFCRL3 genes [10, 42 46]. genes are associated with fertility status in endometriosis. Gynecol Recently, it has been suggested that CYP17, VDR, MUC17, Endocrinol. 2011;27:425–33. COX-2, WNT4, E-cadherin, CYP19, CYP17 , TYK2, NFKB1, 11. Tsuchiya M, Nakao H, Katoh T, Sasaki H, Hiroshima M, Tanaka T, and MUC2 gene variants also contributed to endometriosis- et al. Association between endometriosis and genetic polymor- – phisms of the estradiol-synthesizing enzyme genes HSD17B1 and related infertility [17, 47 55]. CYP19. Hum Reprod. 2005;20:974–8. 12. Vihko P, Isomaa V, Ghosh D. Structure and function of 17beta- hydroxysteroid dehydrogenase type 1 and type 2. Mol Cell Conclusions Endocrinol. 2001;171:71–6. 13. Feigelson HS, McKean-Cowdin R, Coetzee GA, Stram DO, Kolonel LN, Henderson BE. Building a multigenic model of breast Our study demonstrated the HSD17B1 937 G variant as risk cancer susceptibility: CYP17 and HSD17B1 are two important factor for infertility in women with endometriosis at stages I candidates. Cancer Res. 2001;61:785–9. and II. Our genetic study was carried out on a relatively small 14. Trabert B, Schwartz SM, Peters U, De Roos AJ, Chen C, Scholes D, group of infertile women with endometriosis; therefore, the et al. Genetic variation in the sex hormone metabolic pathway and endometriosis risk: an evaluation of candidate genes. Fertil Steril. role of this polymorphism should be further studied in women 2011;96:1401–6.e3. with idiopathic infertility and a larger and independent cohort 15. Wu CH, Yang JG, Chang YJ, Hsu CC, Kuo PL. Screening of a panel of infertile women with endometriosis. of steroid-related genes showed polymorphisms of aromatase genes confer susceptibility to advanced stage endometriosis in the Taiwanese Han population. Taiwan J Obstet Gynecol. 2013;52:485–92. Acknowledgements This study was supported by grant nos. 16. Canis M, Donnez JG, Guzick DS, Halme JK, Rock JA, Schenken 502-01-01124182-07474 and 502-14-01110142-41198, RS, et al. Revised American Society for Reproductive Medicine Poznan University of Medical Sciences. classification of endometriosis: 1996. Fertil Steril. 1997;67:817–21. J Assist Reprod Genet

17. Szczepańska M, Wirstlein P, Skrzypczak J, Jagodziński PP. 37. Olivennes F. Results of IVF in women with endometriosis. J Polymorphic variants of CYP17 and CYP19A and risk of infertility Gynecol Obstet Biol Reprod (Paris). 2003;32:45–7. in endometriosis. Acta Obstet Gynecol Scand. 2013;92:1188–93. 38. Holoch KJ, Lessey BA. Endometriosis and infertility. Clin Obstet 18. Maybin JA, Critchley HO. Steroid regulation of menstrual bleeding Gynecol. 2010;53:429–38. and endometrial repair. Rev Endocr Metab Disord. 2012;13:253–63. 39. D'Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis 19. Rižner TL. The important roles of steroid sulfatase and and subfertility: is the relationship resolved? Semin Reprod Med. sulfotransferases in gynecological diseases. Front Pharmacol. 2003;21:243–54. 2016;7:30. 40. Olive DL, Pritts EA. Treatment of endometriosis. N Engl J Med. 20. Slayden OD. Induced endometriosis in nonhuman primates. Biol 2001;345:266–75. Reprod. 2013;88:43. 41. Sapkota Y, Attia J, Gordon SD, Henders AK, Holliday EG, 21. Hirata T, Osuga Y, Yoshino O, Hirota Y, Harada M, Takemura Y, Rahmioglu N, et al. Genetic burden associated with varying de- et al. Development of an experimental model of endometriosis grees of disease severity in endometriosis. Mol Hum Reprod. using mice that ubiquitously express green fluorescent protein. 2015;21:594–602. Hum Reprod. 2005;20:2092–6. 42. Liao WX, Roy AC, Chan C, Arulkumaran S, Ratnam SS. A new 22. Nair HB, Baker R, Owston MA, Escalona R, Dick EJ, VandeBerg JL, molecular variant of luteinizing hormone associated with female – et al. An efficient model of human endometriosis by induced unop- infertility. Fertil Steril. 1998;69:102 6. posed estrogenicity in baboons. Oncotarget. 2016;7:10857–69. 43. Mafra FA, Bianco B, Christofolini DM, Souza AM, Zulli K, 23. Kitawaki J, Noguchi T, Amatsu T, Maeda K, Tsukamoto K, Barbosa CP. Luteinizing hormone beta-subunit gene (LHbeta) Yamamoto T, et al. Expression of aromatase cytochrome P450 pro- polymorphism in infertility and endometriosis-associated infertility. – tein and messenger ribonucleic acid in human endometriotic and Eur J Obstet Gynecol Reprod Biol. 2010;151:66 9. adenomyotic tissues but not in normal endometrium. Biol Reprod. 44. Zulli K, Bianco B, Mafra FA, Teles JS, Christofolini DM, Barbosa β 1997;57:514–9. CP. Polymorphism of the estrogen receptor gene is related to 24. Huhtinen K, Desai R, Ståhle M, Salminen A, Handelsman DJ, infertility and infertility-associated endometriosis. Arq Bras – Perheentupa A, et al. Endometrial and endometriotic concentrations Endocrinol Metabol. 2010;54:567 71. of estrone and estradiol are determined by local metabolism rather 45. Ruiz LA, Dutil J, Ruiz A, Fourquet J, Abac S, Laboy J, et al. Single- than circulating levels. J Clin Endocrinol Metab. 2012;97:4228–35. nucleotide polymorphisms in the lysyl oxidase-like protein 4 and 25. Henzl MR, Corson SL, Moghissi K, Buttram VC, Berqvist C, complement component 3 genes are associated with increased risk Jacobson J. Administration of nasal nafarelin as compared with oral for endometriosis and endometriosis-associated infertility. Fertil Steril. 2011;96:512–5. danazol for endometriosis. A multicenter double-blind comparative clinical trial. N Engl J Med. 1988;318:485–9. 46. Zhang H, Zhang Z, Li G, Wang S, Zhang S, Xie B. Association of FCRL3 genetic polymorphisms with endometriosis-related infertil- 26. Henzl MR, Long K. Efficacy and safety of nafarelin in the treatment ity risk: an independent study in Han Chinese. Medicine of endometriosis. Am J Obstet Gynecol. 1990;162:570–4. (Baltimore). 2015;94:e1168. 27. Delvoux B, D'Hooghe T, Kyama C, Koskimies P, Hermans RJ, 47. Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Misztal Dunselman GA, et al. Inhibition of type 1 17β-hydroxysteroid de- M, Jagodziński PP. Polymorphic variants in vitamin D signaling hydrogenase impairs the synthesis of 17β-estradiol in endometri- pathway genes and the risk of endometriosis-associated infertility. osis lesions. J Clin Endocrinol Metab. 2014;99:276–84. Mol Med Rep. 2015;12:7109–15. 28. Mori T, Ito F, Matsushima H, Takaoka O, Koshiba A, Tanaka Y, 48. Yang CW, Chang CY, Lai MT, Chang HW, Lu CC, Chen Y, et al. et al. Dienogest reduces HSD17β1 expression and activity in endo- – Genetic variations of MUC17 are associated with endometriosis metriosis. J Endocrinol. 2015;225:69 76. development and related infertility. BMC Med Genet. 2015;16:60. 29. Colette S, Defrère S, Van Kerk O, Van Langendonckt A, Dolmans 49. Cavalcanti V, Ponce TG, Mafra FA, André GM, Christofolini DM, MM, Donnez J. Differential expression of steroidogenic enzymes Barbosa CP, et al. Evaluation of the frequency of G-765C polymor- – according to endometriosis type. Fertil Steril. 2013;100:1642 9. phism in the promoter region of the COX-2 gene and its correlation 30. Christofolini DM, Amaro A, Mafra F, Sonnewend A, Bianco B, with the expression of this gene in the endometrium of women with Barbosa CP. CYP2C19 polymorphism increases the risk of endo- endometriosis. Arch Gynecol Obstet. 2016;293:109–15. – metriosis. J Assist Reprod Genet. 2015;32:91 4. 50. Mafra F, Catto M, Bianco B, Barbosa CP, Christofolini D. 31. Mu X, Du X, Yao K, Zhao J, Bian C, Wang Q, et al. Association Association of WNT4 polymorphisms with endometriosis in infer- between HSD17B1 rs605059 polymorphisms and the risk of uter- tile patients. J Assist Reprod Genet. 2015;32:1359–64. ine diseases: a systemic review and meta-analysis. Int J Clin Exp 51. KangS,LiY,LiB,WangN,ZhouRM,ZhaoXW.Geneticvariation – Pathol. 2015;8:6012 8. of the E-cadherin gene is associated with primary infertility in patients 32. Ntostis P, Agiannitopoulos K, Tsaousis G, Pantos K, Lamnissou K. with ovarian endometriosis. Fertil Steril. 2014;102:1149–1154.e1. Evidence for association of the rs605059 polymorphism of 52. Wang L, Lu X, Wang D, Qu W, Li W, Xu X, et al. CYP19 gene HSD17B1 gene with recurrent spontaneous abortions. J Matern variant confers susceptibility to endometriosis-associated infertility Fetal Neonatal Med. 2015;28:2250–3. in Chinese women. Exp Mol Med. 2014;46:e103. 33. Ashton KA, Proietto A, Otton G, Symonds I, McEvoy M, Attia J, 53. Peluso C, Christofolini DM, Goldman CS, Mafra FA, Cavalcanti V, Gilbert M, Hamann U, Scott RJ. Polymorphisms in genes of the Barbosa CP, et al. TYK2 rs34536443 polymorphism is associated steroid hormone biosynthesis and metabolism pathways and endo- with a decreased susceptibility to endometriosis-related infertility. metrial cancer risk. Cancer Epidemiol. 2010;34:328–37. Hum Immunol. 2013;74:93–7. 34. Setiawan VW, Hankinson SE, Colditz GA, Hunter DJ, De Vivo I. 54. Bianco B, Lerner TG, Trevisan CM, Cavalcanti V, Christofolini HSD17B1 gene polymorphisms and risk of endometrial and breast DM, Barbosa CP. The nuclear factor-kB functional promoter poly- cancer. Cancer Epidemiol Biomark Prev. 2004;13:213–9. morphism is associated with endometriosis and infertility. Hum 35. Shi L, Yang X, Dong X, Zhang B. Polymorphism of HSD17B1 Immunol. 2012;73:1190–3. Ser312Gly with cancer risk: evidence from 66,147 subjects. Twin 55. Chang CY, Chen Y, Lin WC, Chen CM, Chen CP, Lee SC, et al. Res Hum Genet. 2016;19:136–45. MUC2 polymorphisms are associated with endometriosis develop- 36. Brosens I. Endometriosis and the outcome of in vitro fertilization. ment and infertility: a case-control study. BMC Med Genet. Fertil Steril. 2004;81:1198–200. 2012;13:15.